ACC is involved in ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA, which is a rate-limiting step in fatty acid synthesis. This reaction proceeds in two half reactions, that is, a biotin carboxylase reaction and a carboxyltransferase reaction. Malonyl-CoA is a carbon donor in the synthesis and elongation reaction of long chain fatty acids and is also a regulator of the palmitoyl CoA carnitine shuttle system involved in mitochondrial oxidation of long chain fatty acids.
ACC exists as two isozymes, that is, ACC1 present in adipogenic tissues such as liver and fat, and ACC2 present in oxidized tissues such as liver, heart and skeletal muscle. ACC1 and ACC2 are encoded by different genes.
ACC1 is abundantly present in the cytoplasm and controls de novo synthesis of fatty acids. Malonyl-CoA, which is a product thereof, acts as a substrate for fatty acid synthase (FASN) and is used for the biosynthesis of long chain fatty acids, phospholipids, triglycerides (TG) and the like. On the other hand, ACC2 is abundantly present in the mitochondrial outer membrane, and controls fatty acid oxidation. Malonyl-CoA, which is a product thereof, inhibits uptake of fatty acid into mitochondria and inhibits fatty acid oxidation in mitochondria, based on the feedback inhibition of carnitine palmitoyl transferase-1 (CPT-1).
In many cancer cells, de novo fatty acid synthesis is flourishing regardless of the number of exogenous fatty acids compared to normal cells. It is already known that several lipid metabolic enzymes, such as FASN, promote the development and malignancy of cancer, and these are expected to become new target molecules for cancer treatment. It is also known that ACC1 is highly expressed in a wide variety of cancer cells. Therefore, inhibition of the biosynthesis of fatty acid in cancer cells by inhibition of ACC1 is extremely useful for the prophylaxis and treatment of cancer. In fact, as a compound having ACC1 inhibitory activity and cancer cell proliferation inhibitory activity, the compound described in patent document 1 is known.
wherein each symbol is as defined in the document.
On the other hand, ACC1 is present in lipogenic tissues such as liver and fat, and controls fatty acid synthesis. Therefore, inhibition of ACC1 reduces fatty acid synthesis and is extremely useful for the prophylaxis or treatment of metabolic syndrome, obesity, hypertension, diabetes, fatty liver disease, non-alcoholic steatohepatitis (sometimes to be abbreviated as NASH in the present specification), nonalcardiovascular diseases associated with atherosclerosis and the like.
Patent document 2 discloses the following compound having a GPR119 regulating action and useful for the prophylaxis or treatment of diabetes and the like.
wherein each symbol is as defined in the document.
Patent document 3 discloses the following compound having an SMO antagonistic action and useful for the prophylaxis or treatment of cancer and the like.
wherein each symbol is as defined in the document.
Patent document 4 discloses the following compound having an ACC2 inhibitory action and useful for the prophylaxis or treatment of obesity, hepatitis (including NASH), cancer and the like.
wherein each symbol is as defined in the document.
Patent document 5 discloses the following compound having a PI3K inhibitory action and useful for the prophylaxis or treatment of respiratory diseases, cancer and the like.
wherein each symbol is as defined in the document.
Patent document 6 discloses the following compound having an ACC inhibitory action and useful for the prophylaxis or treatment of cancer, NASH and the like.
wherein each symbol is as defined in the document.